Is EPHB4 p.Arg483Trp (c.1447C>T) pathogenic?

EPHB4 p.Arg483Trp (c.1447C>T) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-01). AlphaMissense: likely benign (0.2546); Very rare (popmax 0.00466%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg483Trp (c.1447C>T)?

EPHB4 p.Arg483Trp (c.1447C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg483Trp (c.1447C>T) in the general population?

EPHB4 p.Arg483Trp (c.1447C>T) is very rare (popmax 0.00466%, eas) (gnomAD).

What do computational predictors say about EPHB4 p.Arg483Trp (c.1447C>T)?

AlphaMissense predicts likely benign (score 0.2546) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg483Trp

c.1447C>T · rs747118805 · VCV3224269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2546 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2546	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -11.18	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00466% East Asian · 2/42,926 alleles

Filtering AF 0.000772% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000434%

Overall 0.00108% 17/1,580,658 alleles · very rare exomes 14/1,428,512 · genomes 3/152,146 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00466%	21,463
Finnishnot grpmax-eligible	0.00165%	60,764
African / African-American	0.00136%	73,762
South Asian	0.00116%	86,520
European (non-Finnish)	0.00103%	97,056

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPHB4
Protein: p.Arg483Trp
Coding: c.1447C>T
MANE Select: NM_004444
dbSNP: rs747118805
Type: single nucleotide variant
Location: chr7:100817333 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 483: a β-strand; a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 2 domain

Full EPHB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Arg483Gln Uncertain significance ★★ ⚠ same residue
EPHB4 p.Arg483= Likely benign ★ same residue
EPHB4 c.1870+5G>C Uncertain significance ★★ same condition
EPHB4 p.Ala262Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala345Gly Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala931Thr Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg148Trp Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg310Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ephb4-p-arg483trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown